1,5-Disubstituted-2-pyrrolidinones, -3-pyrrolin-2-ones, and -4-pyrrolin-2-ones

ABSTRACT

Certain 1,5-disubstituted 2-pyrrolidinones, and their ring unsaturated analogs, resemble natural prostaglandins. The compounds are easier to prepare than the prostaglandins since they have at least one fewer center of asymmetry and accordingly fewer isomers are produced. Exemplary is 7-[2-oxo-5-(3-hydroxy-1-oct-1-enyl)-1-pyrrolidinyl]heptanoic acid of the formula:

BACKGROUND OF THE INVENTION 1. Field of the Invention

This invention concerns substituted 2-pyrrolidinones, and theirring-unsaturated analogs, which resemble prostaglandins. The naturalprostaglandins of the E, F and A series have several centers ofasymmetry and are difficult to synthesize. The compounds of the presentinvention have at least one fewer center of asymmetry and are easier toprepare since fewer isomers are obtained.

2. Prior Art

Sedavkina et al, Khim, Geterotsikl. Soedin. 1972, (3), 331-2 have shownthe preparation of 5-alkyl-N-(β-hydroxyethyl)-2-pyrrolidinones from thecorresponding γ-ketocarboxylate esters, ethanolamine and Raney nickel.These 2-pyrrolidinones are not the compounds of this invention.

STATEMENT OF THE INVENTION

There have now been discovered the prostaglandin-like compounds of theformula: ##SPC2##

A is --CH=CH--, --C.tbd.C--, --CH₂ --, or --C₆ H₄ --(o, m, or p);

B is -CH₂ --, >C=O or ##EQU1## D is --CH₃, -- CF₂ CH₃, or --CF₃ ; Y is Hor OR⁵ ;

R is H, alkyl (straight or branched chain of 1-10 carbon atoms),cycloalkyl, aryl, aralkyl, alkaryl, or a physiologically acceptablecation;

R¹, r² and R³ are individually H, CH₃ or C₂ H₅ ;

R⁴ is H, alkyl of 1-4 carbon atoms, vinyl or ethynyl;

R⁵ and R⁶ are individually H, CH₃, C₂ H₅, tetrahydropyranyl (THP),benzyl, acyl of 1-4 carbon atoms or trialkylsilyl in which alkyl isstraight or branched chain of 1-10 carbon atoms;

m and n are whole numbers in the range 1-8; a, b and c (the dottedlines) are optional additional bonds with the provisos that:

If c is present, only of a and b is present;

If c is absent, only one of a and b is present and A is not --C.tbd.C--;

if a or b is present, Y is H;

if R is tert-butyl, Y is H, OTHP or trialkylsilyl and R⁶ is not THP.

Terms used in the definition of R above include the following:

Cycloalkyl of 3-8 carbon atoms, including cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.

Aryl of 6-14 carbon atoms, including particularly phenyl, halophenyl(halo = F, Cl, Br, I), sulfino-, sulfo-, sulfamoyl-, sulfanilyl-,sulfoamino- and sulfanilamido-phenyl.

Aralkyl of 7-10 carbon atoms, including benzyl, phenethyl and4-phenylbutyl.

Alkaryl of 7-10 carbon atoms, including tolyl, xylyl and duryl.

Physiologically acceptable cation, including particularly lithium,sodium, potassium, rubidium, cesium, ammonium and the manyphysiologically acceptable substituted ammonium cations such astriethylammonium, tetraethylammonium, tetrabutylammonium,tetrapropylammmonium and tris(hydroxymethyl)methylammonium.

The compounds of the above formula can be prepared by the followinggeneral scheme: ##SPC3##

Y = h, tetrahydropyranyloxy or trialkylsilyloxy;

X = br, I, tosyl or other leaving group. A leaving group is one which isreadily displaceable from carbon in an exchange reaction. Other examplesof such are chloride, methanesulfonate, p-nitrobenzene sulfonate andtrifluoroacetate. ##SPC4##

In this step when Y on compound 18 is tetrahydropyranyloxy (OTHP) ortrialkylsilyloxy, it becomes OH in compound 19. ##SPC5##

In this step when Y on compound 19 is OH, it becomes OR⁵ in compound 20.

Alternatively, particularly when R⁴ is other than H, the followingsequence may be used to advantage: ##SPC6##

The compound of type 11 where Y = H and the optional double bond is notpresent is made by esterification of commercially-available pyroglutamicacid (see Ex. 1, Part A). The compound where Y = OTHP is made by heatingthe known dimethyl 3-hydroxy glutamate in alcohol, followed by treatmentwith dihydropyran and an acid catalyst (standard conditions for thepreparation of a tetrahydropyranylated alcohol): ##SPC7##

If, rather than being treated with dihydropyran, the intermediate cyclicalcohol is dehydrated (by treatment with strong base,dicyclohexylcarbodimide, or mesyl chloride sulfur dioxide, for example),or converted to, for example, the corresponding bromide (using PBr₃ ortriphenylphospine dibromide) followed by dehydrohalogenation, compound11 with Y = H and the optional double bond present is produced: ##SPC8##

As the product is a mixture in which the predominance of a particulardouble bond isomet depends on the precise elimination conditions, thedouble bond is represented as a dotted line. The compounds are separablebut need not be separated for subsequent reaction.

The lactams 11 are then N-alkylated with XCH₂ (A)-(CH₂)_(m) CO₂ t-Buusing sodium hydride as the base and dimethylformamide as the solvent.Other base/solvent systems can be used. The alkylating agents XCH₂(A)-(CH₂)m-- CO₂ t-Bu where X = Br and A = CH₂ are made by the standardmethod [e.g., A. L. McCloskey et al., Org. Syn. Coll., Vol. 4, 261(1963)] from the commercially-available ω-bromo acids and isobutene. Thecompounds where A = --C.tbd.C-- are made by the same esterificationtechnique from the corresponding ω-bromo alkynoic acids. These acids areprepared by the method of Ferdinandi and Just [Can. J. Chem., 49, 1070(1971)] from commercially-available materials. Reduction of thesetert-butyl ω-haloalkynoates with hydrogen over Lindlar catalyst [H,Lindlar, Helv. Chim, Acta, 35, 446 (1952)] or, preferably, the Crammodification of it [D. J. Cram and N. L. Allinger, J. Am. Chem. Soc.,78. 2518 (1956)]gives the compound with A = --CH= CH-- in the desiredcis-modification. Alternatively, Brown's P-2 nickel boride catalyst [H.C. Brown and C. A. Brown, J. Am. Chem. Soc., 85, 1005 (1963)] may beused for this purpose.

The compounds where A = o or p-phenylene are prepared bybromomethylation of the commercially-available ω-arylalkanoic acids.This transformation is accomplished by treatment of the acid withhydrogen bromide and formaldehyde (as paraformaldehyde) under standardconditions (see, for example, Organic Reactions, Vol. I, Chap. 3, p. 72,John Wiley and Sons, N.Y., 1942), producing both the ortho and paraisomers which are, however, readily separable. Best yields of thebromomethylated products are obtained when the reaction is carried outin the absence of added zinc salts.

The choice of X = Br for the alkylating agents is made on the basis ofease of preparation and ready displaceability. With X = Cl the compoundsare considerably less reactive, while X = I (prepared from the compoundswith X = Br by the Finkelstein halide interchange reaction) are somewhatmore difficult to prepare and to handle. The bromine atom can bedisplaced by hydroxide and the resulting alcohol converted to itstoluenesulfonate or methanesulfonate derivative for displacement, butlittle would be gained by these additional steps.

In the alkylation reaction by which compounds of type 11 are convertedto compounds of type 12, the base employed is preferably anonnucleophilic base with a pKb of 19 or greater. Such bases include thehydrides of the alkali metals, particularly Li, Na, K, Rb and Cs; alkalimetal alkyls such as methyllithium; alkali metal triarylmethides such aspotassium triphenylmethide and hindered alkali metal amides andalkoxides such as lithium diisopropylamide and potassium tert-butoxide.

To avoid undue loss of base in side reaction with water, it is preferredthat the reactants and solvent be reasonably anhydrous. Solvent used asreaction media should be inert to the reactants and products. Suitablemedia include polar aprotic organic solvents such as dimethylformamide,hexamethylphosphoramide, tetramethylenesulfone, and ethers such asdimethyl ether, diethyl ether, dimethoxyethane and tetrahydrofuran.

The molar proportions in which the lactam, alkylating agent and base arebrought together are not critical, since any proportion in which allthree are brought together will yield at least some of the correspondingcompound of type 12. Best yields are obtained using substantiallyequimolar proportions of alkylating agent and base with a slight molarexcess of lactam 11. Temperatures in the alkylation reaction range from-50° to 140°C. and temperatures in the range from -50° to 120°C. arepreferred. Pressure is not a critical variable and pressures both aboveand below atmospheric pressure may be employed.

Reduction of the 5-carbomethoxy group in 12 to the 5-formyl group in 13is accomplished by the use of the selective, soluble reducing agentsodium bis(2-methoxy-ethoxy) aluminum hydride, developed by J. Vit[Eastman Organic Chem. Bull., 42 (3), 8 (1970)] and marketed by Eastmanas an 80% solution in benzene under the tradename Vitride. With thisreducing agent, the carbomethoxy group is reduced while thecarbotert-butoxy group is not. The tert-butyl group protection of theterminal carboxyl moiety is presently viewed as unique in providing bothresistance to nucleophilic displacement in the conversion of 11 to 12and resistance to reduction in the conversion of 12 to 13 while beingrelatively easily removed when desired (conversion of 18 to 19). Thereducing agent also seems to offer a unique combination of selectivityand ease of handling. Use of other reducing agents such as lithiumaluminum hydride would necessitate in conveniences such as inverseaddition and low solubility while not promising any improvement inselectivity.

In the reduction reaction by which esters of type 12 are converted toaldehydes of type 13 by the action of the reducing agent NaAlH₂ (OCH₂CH₂ OCH₃)₂, the reactants and solvent are preferably substantiallyanhydrous to avoid loss of the reducing agent in a side reaction withwater. The solvent should be liquid, capable of dissolving the reactantsat the reaction temperature and inert to the reactants and products. Lowmelting ethers such as dimethyl ether, diethyl ether and tetrahydrofuranare preferred as solvents.

The molar proportions in which the ester of type 12 and the reducingagent may be brought together in the reduction reaction is not critical,since any proportions in which the two are brought together will yieldat least some of the product aldehyde of type 13. It is preferred toemploy either equimolar quantities or a slight molar excess of the esterof type 12. The temperature for the reduction reaction should range from-90° to -40°C. and temperatures in the range from -90° to -50°C. arepreferred. Pressure is not a critical veriable and pressures both aboveand below atmospheric pressure may be used.

The conversion of 13 to 14 is accomplished by the Emmons modification ofthe Wittig reaction [W. S. Wadsworth, Jr. and W. D. Emmons, J. Am. Chem.Soc., 83, 1733 (1961)], first shown to be useful for prostaglandinsynthesis by Corey [E. J. Corey et al., J. Am. Chem. Soc., 91, 5675(1969)]. The phosphonates are not unique in their usefulness for thistype of conversion (the more usual phosphine-type Wittig reagents canand have been used), but they are easy to use and give high yields ofspecifically the transolefinic product 14. The phosphonates,

    (CH.sub.3 O).sub.2 P(O)CHR.sup.1 COCR.sup.2 R.sup.3 (CH.sub.2).sub.n D,

can be made by any one of three methods, that of Arbusov [B. A. Arbusov,Pure Appl. Chem., 9, 307 (1964)], Corey [E. J. Corey and G. T.Kwiatkowski, J. Am. Chem. Soc., 88, 5654 (1966)] or Grieco [P. A. Griecoand R. S. Finkelhor, J. Org. Chem., 38, 2909 (1973)]. The Corey methodis preferable because the necessary starting materials are most readilyavailable.

The conversion of 13 to 14 is best done at reduced temperature to avoidside-reactions such as self-condensation of the aldehyde molecules. Useof a large excess of phosphonate salt would also accomplish thispurpose, but with loss of convenience and economy.

The α,β-unsaturated ketones 14 provide a branch point in the synthesis.Reaction of the ketone carbonyl with Grignard reagents provides thetertiary allylic alcohols 15. Alkyl lithium reagents corresponding tothe Grignards would be expected to give similar results but also moreextensive side-reactions due to their higher inherent reactivity. For R⁴= ethynyl the ketone is reacted with ethynyllithium (preferably as itsethylenediamine complex). Ethynylsodium can also be used, but it issomewhat less suitable due to its greater tendency toward conjugateaddition.

For R⁴ = H, reduction of the unsaturated ketone to the allylic alcoholis best accomplished with zinc borohydride, a reagent first described byGensler [W. J. Gensler et al., J. Am. Chem. Soc., 82, 6074 (1960)].Other complex metal hydrides in general are either too reactive (e.g.,lithium aluminum hydride) or give extensive conjugate reduction (e.g.,sodium borohydride). If an optically active alcohol is desired, a highlyhindered optically active borane such as that described by Corey [E. J.Corey et al., J. Am. Chem. Soc., 94, 8616 (1972)] is used to advantagefor this reduction. Finally, if it is desired that optional bond (c) notbe present, the double bond conjugated to the ketone carbonyl can bereduced using sodium metal dissolved in tetrahydrofuran withtert-butanol added (for discussion see: H. O. House, "Modern SyntheticReactions", W. A. Benjamin, Menlo Park, California, 1972, p. 145 ff).Such a reaction also reduces double bond (a) or (b) should it be presentand converts A = --C.tbd.C-- to a trans double bond and is therefore notsuitable if these changes are not desired. The resulting saturatedketone is then treated just as the unsaturated one was, converting it toa tertiary alcohol by treatment with a Grignard reagent orethynyllithium or to a secondary alcohol by reduction. In this case zincborohydride is unnecessary, since conjugate reduction is no problem, andmore readily-available sodium borohydride may be employed.

Should it be desired that R⁶ be other than H, the alcohol is treatedwith an alkylating or acylating agent in the presence of a base.Alkylation is simply an example of the classical Williamson ethersynthesis using a tertiary alkoxide as the base and methyl iodide, ethyliodide, or a benzyl iodide as the alkylating agent. Acylation would beaccomplished by using the desired acyl chloride and an equivalent of atertiary amine or metal carbonate or oxide to neutralize the liberatedhydrogen chloride.

Treatment of compound 18 ( or 17, if R⁶ is to remain H) with anhydroustrifluoroacetic acid cleaves the tert-butyl ester group so the terminalcarboxyl group can be esterified with another alcohol. Cleavage of thetert-butyl group is also accomplished with strongly acidic catalyst suchas hydrogen chloride in moist chloroform or boron trifluoride etherateif desired, but the temperature during the cleavage should remain at 0°Cor below in order to minimize elimination of the --OR⁶ group. The finalesterification of the carboxyl group is accomplished by the use of anexcess of the alcohol ROH and dicyclohexyl carbodiimide as theesterification reagent. Other esterification reagents can be used, suchas carbonyldiimidazole or thionyl chloride.

Finally, if Y = --OH and it is desired that R⁵ not be H, 19 is treatedin the same manner as 15-17 with an alkylating or acylating agent andthe appropriate base.

Specific Embodiments of the Invention

In the illustrative examples which follow, parts and percentages are byweight unless otherwise indicated.

EXAMPLE 1 Part A - Tert-butyl 7-(2-Oxo-5-methoxycarbonyl-1-pyrrolidinyl)heptanoate (1) ##SPC9##

Into a thoroughly dried 500 ml flask filled with dry nitrogen was placed5.0 g of 57% sodium hydride/oil dispersion (2.85 g of sodium hydride,0.120 mole). The dispersion was washed three times with 10 ml portionsof dry petroleum ether, then dried under a nitrogen stream. To the dryhydride was added 200 ml of dimethylformamide (distilled from calciumhydride, stored over 4A molecular sieves) with stirring (magneticspinbar). To the suspension was added dropwise over 15 minutes a mixtureof 16.0 g of methyl pyroglutamate (0.112 mole) and 28.0 g of tert-butyl7-bromoheptanoate (0.105 mole) in 30 ml of dry dimethylformamide. Afterthe addition was complete, the mixture was left to stir at ambienttemperature for about 63 hours. The reaction was fairly vigorous,forming a dark green solution which gradually became yellow-brown. Thereaction mixture was poured into a well-stirred mixture of 1200 ml ofwater and 300 ml of diethyl ether, separated, and the aqueous phaseextracted twice more with 200-ml portions of ether. The etherealextracts were combined, washed three times with 300-ml portions ofwater, once with 200 ml of saturated sodium chloride solution and driedover magnesium sulfate/calcium sulfate. Removal of the ether (rotaryevaporator) gave 28.8 g of a light yellow oil, which was distilled(short-path apparatus: 152°-155°/0.3 μ Hg) to yield 26.2 g (76%) of 1 asa colorless oil. IR: 1750, 1740, 1700, 1415, 1395, 1385, 1210, 1155 cm⁻¹ ; pmr: δ 4.25 (m, 1), 3.76 (s, 3), 3.55 (m, 1), 2.95 (m, 1), 2.22 (m,1), 1.46 (s) and 1.40 (broad m, 17 total).

Part B - Tert-butyl 7-(2-Oxo-5-formyl-1-pyrrolidinyl)heptanoate (2)##SPC10##

To a solution of 10.00 g of diester lactam 1 (30.5 mmoles) in 200 ml ofdry tetrahydrofuran (THF) under nitrogen at -78°C was added dropwise asolution of 5 ml of "Red-Al" (70% solution of sodiumbis(2-methoxyethoxy) aluminum hydride in benzene, Aldrich ChemicalCompany) followed by an additional 10 ml of THF. The mixture was stirred72 hours at -78°C and poured cold into a mixture of 500 ml of water and300 ml of ether. After another 30 minutes of stirring, the organic phasewas separated, washed three times with water, once with saturated NaCland dried over magnesium sulfate/calcium sulfate. The oil obtained afterevaporation of the ether was heated 0.5 hour at 100°C/0.001 Torr toremove water and then distilled to yield 4.89 g (54% yield) of 2 in theform of a yellow mobile oil. pmr: δ 9.58 (d, J = 2.5 Hz, 1), 4.2 (m, 1),2.8-3.8 (broad m, 2), 2.3 (m, 6), 1.45 (s and broad m, 17). A largersample of 2 prepared essentially by scaling up the above procedure gavethe following additional measurements. IR: 1720, 1660, 1640 (sh), 1450,1415, 1385, 1360, 1250, 1150, 1100, 845 cm⁻ ¹. High-resolution massspectrum: M + meas. m/e 268.1918; calcd for C₁₅ H₂₆ NO₃ : 268.1911.

The larger sample was dried by azeotropic distillation of a benzenesolution. The material thus obtained was satisfactory for furtherreaction, thus substantially increasing the yield of product which istemperature-sensitive and was partially destroyed on distillation.

Part C - Tert-butyl 7-[2-Oxo-5-(3-oxo-1-oct-1-enyl)-1-pyrrolidinyl]heptanoate (3) ##SPC11##

To a solution of 0.724 g of dimethyl (2-oxohepytyl)phosphonate and 0.137g of a 57% mineral oil dispersion of sodium hydride (Callery ChemicalCompany) in about 200 ml of ethylene glycol dimethyl ether (glyme) at-30°C was added 1.00 g of aldehyde 2. The mixture was stirred for 3hours at -25°C and then drowned in water. The resulting mixture wasextracted with ether. The ether extract was dried over anydrousmagnesium sulfate/calcium sulfate and chromatographed on silica gel toobtain 0.870 g of the unsaturated ketone 3 in the form of a colorlessoil (66% yield). It showed ir absorption at 990 cm⁻ ¹ and pmr: δ 6.63 (dof d, J = 7.5 and 17 Hz, 1), 6.20 (d, J = 17 Hz, 1), 4.24 (m, 1) 3.6(broad m, 1), 2.3 (broad m, 10), 1.45 (s, 9), 1.4 (broad m, 6), 0.90(broad t, J = 6 Hz, 3). High-resolution mass spectrum: M+ meas. m/e337.2215; calcd for C₁₉ H₃₁ O₄ N: 337.2251.

EXAMPLE 2 Tert-butyl7-[2-Oxo-5-(3-hydroxy-1-oct-1-enyl)-1-pyrrolidinyl]heptanoate (4)##SPC12##

In 50 ml of a 5:1 mixture of diethyl ether, glyme under nitrogen wasdissolved 2.00 g of ketone 3 (5.08 mmoles) and the solution was heatedto reflux. To this solution was added 28.2 ml of ca. 0.45M zincborohydride/ether solution (10.0 equiv.) by syringe and reflux wascontinued for 2.5 hours. The solution became cloudy within 5 minutes andremained so throughout the reaction. The reaction mixture was thenpoured into a stirred mixture of 150 ml of ether/150 ml of water. Thereaction flask was rinsed out with this mixture. To the ether/watermixture was added sufficient saturated aqueous ammonium chloridesolution to dissolve the precipitated zinc salts. The layers wereseparated and the aqueous layer was extracted with an additional 100-mlportion of ether. The ethereal extracts were combined, washed threetimes with water, once with saturated sodium chloride solution and driedover magnesium sulfate/calcium sulfate. The solution was filtered andconcentrated (rotary evaporator) to give 1.817 g of 4 (90%) as a lightyellow oil. IR: 3400 (broad), 1725, 1680, 1455, 1415, 1388 (sharp),1365, 1255, 1150, 970 (trans--CH=CH--), 850 cm⁻ ¹ ; nmr: δ 5.63 (m,strong secondary coupling effects, 2), 4.1 (broad m, 2), 3.03 (broad,1), 2.2 (broad m, 8), 1.45 (s, 9), 1.4 (broad m, 16), 0.88 (broad t, 3).High-resolution mass spectrum: M⁺ meas. m/e 395.2901; calcd for C₂₃ H₄₁NO₄ : 395.3035.

EXAMPLE 3 7-[2-Oxo-5-(3-hydroxy-1-oct-1-enyl)-1-pyrrolidinyl]-heptanoicAcid (5) ##SPC13##

Ester 4 (0.280 g, 0.71 mmole) was dissolved in 20 ml of chloroform. Tothe solution was added 2-3 drops of water. Hydrogen chloride gas waspassed into the vigorously stirred mixture over a 90-minute period, withchloroform added periodically to maintain the solvent level. During thereaction period the mixture became cloudy and yellow. The reactionmixture was then concentrated on a rotary evaporator and the resultingoil was taken up in 20 ml of ether. The ethereal solution was extractedthree times with 20-ml portions of 5% sodium bicarbonate solution. Thebicarbonate extracts were combined, acidified (ca. pH 2) withconcentrated hydrochloric acid and the resulting milky suspensionextracted three times with 20-ml portions of ether. The etherealextracts were combined, washed three times with water, once withsaturated sodium chloride solution and dried over magnesiumsulfate/calcium sulfate. Evaporation of the ether gave 0.212 g of crude5 (88%) as a light yellow oil. The oil was taken up in ca. 2 ml of ethylacetate from which it crystallized upon standing three days in a -30°Cfreezer. The white, microcrystalline powder (0.170 g, 71%) melted overthe range 83°-97°C, not unusual for a mixture of diastereomers. Some ofthe crystals were observed to melt as high as 103°C, however, so thatthere is a possibility that repeated crystallizations from more dilutesolution might effect a separation of the two compounds. IR (CHCl₃):3600-2400 (--CO₂ H and --OH), 1720 (broad), 1665, 1455, 1415, 1375, 1205(broad), 1160 (broad), 975 cm⁻ ¹ (trans--CH=CH--); nmr: δ8.38 (broad s,-CO₂ H and --OH with intramolecular exchange, 2), 5.6 (m, 2), 4.12(broad m, 2), 2.3 (broad m, 6), 1.38 (broad m, 18), 0.9 (broad t, 3).High-resolution mass spectrum of bis-tri-methylsilylated derivative, M⁺meas. m/e 468.2981; calcd for C₂₄ H₄₆ O₄ NSi₂, 468.2963.

EXAMPLE 4 Tert-butyl7-[2-Oxo-5-(3-hydroxy-3-methyl-1-oct-1-enyl)-1-pyrrolidinyl]heptanoate(6) ##SPC14##

Into a thoroughly dried 50-ml three-neck round bottom flask undernitrogen equipped with a magnetic stirring bar was injected via rubberserum cap a solution of 200 mg of ketone 3 (9.495 mmoles) in 10 ml ofanhydrous diethyl ether. The solution was cooled to -40°C and 1.0equivalent methylmagnesium bromide solution in ether (0.19 ml of 2.6 Msolution) was added, causing immediate formation of a white precipitate.The mixture was left to stir overnight, coming to -25°C. During thistime the ether evaporated leaving a white solid adhering to the flask.The contents of the flask were taken up in 20 ml of ether and 30 ml ofwater and transferred to a separatory funnel where the mixture wasneutralized (not acidified) with 3 drops of glacial acetic acid. Theorganic phase was separated, washed twice with water, dried overanhydrous sodium sulfate and concentrated on a rotary evaporator toyield 0.194 g of crude 6 (93.5%) as a light yellow oil. Analysis of theproduct by thin-layer chromatography (Silica gel G/ethyl acetate) showedmainly one spot, R_(f) 0.35, with the other spots being barelydiscernible. IR: 3400 (broad, --OH), 1725 (ester CO), 1670 (amide CO),1455, 1420, 1390 (sharp), 1365, 1255, 1155, 975 (trans--CH=CH--), 850cm⁻ ¹ ; nmr:δ5.67 (m, 2), 4.05 (broad m, 1), 2.3 (broad m, 6), 1.62,1.28 and 1.6-1.1 (--C(CH₃)₃, --CH₃, and -CH₂ 's superimposed, --21),0.88 (broad t, 3). High-resolution mass spectrum, M⁺ meas. m/3 409.3202;calcd for C₂₄ H₄₃ O₄ N: 409.3190.

The compounds of this invention mimic or antagonize the prostaglandins.The apparent contradiction in this statement is resolved by consideringthe fact that PGE₁, a natural prostaglandin, reverses or antagonizes thecontracting action of PGF₂ .sub.α, another prostaglandin, or bronchialsmooth muscle. In a similar manner, compound 5 (Example 3) contracts ratuterine smooth muscle (at 50 ng/ml) in the same way as PGE₁ and isantagonized in this action by compound 4 Example 2). Compound 4 (thetert-butyl ester of 5) also antagonizes PGE₁ -induced smooth musclecontractions (at 10μg/ml for 50% inhibition). Both compounds 4 and 5are, however, active as topical and injectable antiinflammatory agentswith nearly the same level of activity. This type of behavior isbelieved to be related to prostaglandin antagonism. Thus, any of thecompounds may be both a prostaglandin mimic and a prostaglandinantagonist depending on the biological system being considered.

The acid 5 has shown activity both as a topical antiinflammatory agent(against croton oil-induced inflammation of rat and mouse ears at 2-3mg/ear) and as a systemic antiinflammatory agent (as an intraperitonealinjection against adjuvant-induced arthritis in rats at 50 mg/kg). Theester 4 is also active, though slightly less so, in both of these tests.This activity is thought to stem from antagonism to indigenousprostaglandins, implicated as primary mediators of inflammation.

Compound 5 has shown activity in cutting off gastrin-induced gastricacid secretion (suggesting utility as an antiulcerogenic medicament) andas an antagonist to histamine-induced bronchoconstriction (suggestingutility as a bronchodilator/antiasthmatic drug).

Other utilities cited for prostaglandins and the present prostaglandinanalogs include use as hypotensives, blood platelet aggregationinhibitors, nasal decongestant, antifertility agents, abortifacient andparturition agents, sedatives, analgesics, and spasmolytics.

Using the general scheme described in detail above a series of tables ofexamples has been constructed on the following basis:

Three representative starting materials were chosen for column A. Allthree are methyl esters mostly for convenience and ease of preparation-- the ethyl or propyl esters would do as well. Compound (c) is shownwith two partial double bonds to indicate that it is a mixture of thetwo possible isomers.

The compounds of column B, which are to be combined with those of A inthe manner shown in the general scheme, are all bromides, again as amatter of convenience and ease of preparation. The iodides, or themethanesulfonate or toluenesulfonate derivatives of the correspondingalcohols, and possibly the chlorides, are equally useful in thisreaction. All of the compounds are tertiary butyl esters because thisfunctionality combines ease of preparation with resistance to thereducing conditions of the next reaction and is thus more or less uniquein this respect.

Combination of each of the compounds of column A with each of thecompounds of column B gives the compounds of column C.

Reduction of each of the compounds of column C with sodiumbis(2-methoxyethoxy) aluminum hydride in tetrahydrofuran at -78°C giveseach of the compounds of column D. Other reducing agents, e.g.,diisobutyl aluminum hydride, lithium aluminum hydride or aluminumhydride, might be useful, but offer no advantage.

Combining each of the compounds of column D with each phosphonatereagent or reagents entered under the corresponding letter in column Egives the compounds of column F. Thus, for example, the compound ofentry (a), column D, is combined with the compound of entry (a) 1.,column E, to give the compound of entry (a), column E. Compound (a),column D, with compound (a)2., column E, gives compound (b), column F.The compounds of column E are all dimethyl phosphonates as a matter ofconvenience, ease of synthesis and availability of the necessaryprecursors. Other dialkyl (and possibly diaryl) phosphonates are equallyuseful for this reaction. The triaryl- or trialkylphosphoniumhalide-type Wittig reagents, e.g., 0₃ P^(+-CH) ₂ CO(CH₂)₄ CH₃ Br⁻, arealso useful in this transformation, but with some loss in convenience ofuse and ease of preparation.

Treatment of each of the compounds of column F with the reagent orreagents listed under the same letter in column G gives each of thecompounds of column H. Zinc borohydride was chosen as the standardreducing agent because it is relatively easy to make and use andrelatively free of the objectionable side-reaction (unlike, forinstance, sodium borohydride) of reduction of the double bond conjugatedto the ketone moiety. Highly sterically-hindered and/or optically activeboranes are also useful, particularly for the production of a singleabsolute configuration. Lithium tri-t-butoxy aluminum hydride oraluminum hydride are not as convenient or selective in this reduction.Catalytic reduction can be used, but only at the expense of other sitesof unsaturation in the molecule. The use of a dissolving metal reagent,sodium-tetrahydrofuran (THF)-tert-butanol (t-BuOH), is illustrated incertain examples for the reduction of the α,β-unsaturated ketone moietyto the saturated alcohol. This reagent can be substituted for bylithium-THF-t-BuOH of lithium-liquid ammonia, but with some loss inselectivity. Acetylenic (--C.tbd.C--) linkages and unsaturations in thepyrrolidone ring are reduced by this reagent and are thus incompatiblewith its use in this synthesis. The Grignard reagents shown in column Gare the alkyl magnesium bromides for convenience and ease ofpreparation. The corresponding chlorides and iodides are equally useful.The corresponding alkyl lithium reagents are less useful because theyare inherently much more reactive and thus less selective than theGrignard reagents. An exception to this is the acetylenic lithiumreagent which is the material of choice for alkynylations.

Treatment of each of the compounds of column H with the alkylating oracylating agent R⁶ X (X = I for alkylating agents and = Cl for acylatingagents) and appropriate base shown in column I yields the compounds ofcolumn J.

The compounds of column J, when treated with trifluoracetic acid at 0°Close isobutene to give the corresponding acids (R = H). If this is thedesired product, no entry is made in column K. Other strongly acidiccatalysts can also be used, but care must be exercised so as to notcause dehydration if R⁶ = H. A strongly acidic ion-exchange resin suchas one of the Dowex 50-X series is useful for this transformation.[Since tetrahydropyranyl ethers are liable under the conditionsnecessary to remove the tert-butyl group, all the entries in column Jwith Y = --OTHP give entries in column L with Y = --OH.] If it isdesired that R be other than H, the acids are treated with the alcoholROH or the salt R^(+OH) ⁻ or R^(+Cl) ⁻ and, in the case of the alcohols,an esterification catalyst such as dicyclohexylcarbodiimide,carbonyldiimidazole or thionyl chloride. If the salts R^(+Cl) ⁻ areused, an equivalent of nonnucleophilic base, such as triethylamine or ametal carbamate or oxide, is also used to take up the liberated hydrogenchloride. The alcohol or salt are shown in column K, but the catalyst orbase are omitted. The products of the esterification or neutralizationare shown in column L.

Finally, if Y = -OH and it is desired that R⁵ be other than H, thecompounds of column L are alkylated or acylated as described above forcolumn J with the reagents shown in column M to give the entries incolumn N. In addition, dihydropyran and an acid catalyst can be used ifR⁵ = THP is desired.

                                      TABLE I                                     __________________________________________________________________________       A                          B                                               __________________________________________________________________________                              a)  BrCH.sub.2 (CH.sub.2).sub.5 CO.sub.2 t-BU       a)                                                                                                      b)  BrCH.sub.2 C.tbd.C(CH.sub.2).sub.3 CO.sub.2                                   t-Bu                                                                      c)  BrCH.sub.2 CH=CH(CH.sub.2).sub.3 CO.sub.2                                     t-Bu                                            b)                                                                                                      d)  BrCH.sub.2 CH.sub.2 CO.sub.2 t-Bu                                         e)  BrCH.sub.2 CH=CH(CH.sub.2).sub.6 CO.sub.2                                     t-Bu                                            c)                                                                                                      f)  --(CH.sub.2).sub.2 CO.sub.2 t-Bu                   C                          D                                               __________________________________________________________________________    a)                        a)                                                  b)                        b)                                                  c)                        c)                                                  d)                        d)                                                  e)                        e)                                                  f)                        f)                                                  g)                        g)                                                  h)                        h)                                                  i)                        i)                                                  j)                        j)                                                  k)                        k)                                                  l)                        l)                                                  m)                        m)                                                  n)                        n)                                                  o)                        o)                                                  p)                        p)                                                  q)                        q)                                                  r)                        r)                                                     E                          F                                               __________________________________________________________________________    a) 1. (CH.sub.3 O).sub.2 P(O)CH.sub.2 CO(CH.sub.2).sub.4 CH.sub.3                                       a)                                                     2. (CH.sub.3 O).sub.2 P(O)CH.sub.2 COC(CH.sub. 3).sub.2 (CH.sub.2).sub.       3 CH.sub.3             b)                                                     3. (CH.sub.3 O).sub.2 P(O)CH.sub.2 CO(CH.sub.2).sub.4 CF.sub.3                                       c)                                                     4. (CH.sub.3 O).sub.2 P(O)CH.sub.2 CO(CH.sub.2).sub.3 CF.sub.2                CH.sub.3               d)                                                     5. (CH.sub.3 O).sub.2 P(O)CH.sub.2 CO(CH.sub.2).sub.8 CH.sub.3                                       e)                                                  b) 1. (CH.sub.3 O).sub.2 P(O)CH.sub.2 COC(CH.sub.3).sub.2 (CH.sub.2).sub.3        CF.sub.3              f)                                                     2. (CH.sub.3 O).sub.2 P(O)CH(CH.sub.3)CO(CH.sub.2).sub.6 CF.sub.2             CH.sub.3               g)                                                     3. (CH.sub.3 O).sub.2 P(O)CH.sub.2 CO(CH.sub.2).sub.4 CH.sub.3                                       h)                                                     4. (CH.sub.3 O).sub.2 P(O)CH.sub.2 CO(CH.sub.2).sub.8 CF.sub.3                                       i)                                                  c) 1. (CH.sub.3 O).sub.2 P(O)CH.sub.2 CO(CH.sub.2).sub.4 CH.sub.3                                       j)                                                  c) 2. (CH.sub.3 O).sub.2 P(O)CH.sub.2 COC(CH.sub.3).sub.2 (CH.sub.2).sub.3        CH.sub.3              k)                                                     3. (CH.sub.3 O).sub.2 P(O)CH.sub.2 COC(CH.sub.3).sub.2 (CH.sub.2).sub.3        CF.sub.3              l)                                                     4. (CH.sub.3 O).sub.2 P(O)CH.sub.2 CO(CH.sub.2).sub.3 CF.sub.2                CH.sub.3               m)                                                     5. (CH.sub.3 O).sub.2 P(O)CH.sub.2 CO(CH.sub.2).sub.8 CF.sub.3                                       n)                                                  d) 1. (CH.sub.3 O).sub.2 P(O)CH.sub.2 CO(CH.sub.2).sub.4 CH.sub.3             d) 2. (CH.sub.3 O).sub.2 P(O)CH.sub.2 COCH(C.sub.2 H.sub.5)(CH.sub.2).sub.       2 CF.sub.3             p)                                                  e) 1. (CH.sub.3 O).sub.2 P(O)CH(CH.sub.3)CO(CH.sub. 2).sub.6 CF.sub.2            CH.sub.3               q)                                                     2. (CH.sub.3 O).sub.2 P(O)CH.sub.2 CO(CH.sub.2).sub.4 CF.sub.3                                       r)                                                  f) 1. (CH.sub.3 O).sub.2 P(O)CH.sub.2 CO(CH.sub.2).sub.4 CH.sub.3                                       s)                                                     2. (CH.sub.3 O).sub.2 P(O)CH.sub.2 COC(CH.sub.3).sub.2 (CH.sub.2).sub.3        CH.sub.3              t)                                                  f) 3. (CH.sub.3 O).sub.2 P(O)CH.sub.2 COC(CH.sub.3).sub.2 (CH.sub.2).sub.3        CF.sub.3              u)                                                     4. (CH.sub.3 O).sub.2 P(O)CH.sub.2 CO(CH.sub.2).sub.4 CF.sub.3                                       v)                                                     5. (CH.sub.3 O).sub.2 P(O)CH.sub.2 CO(CH.sub.2).sub.3 CF.sub.2                CH.sub.3               w)                                                     6. (CH.sub.3 O).sub.2 P(O)CH.sub.2 CO(CH.sub.2).sub.8 CH.sub.3                                       x)                                                  g) 1. (CH.sub.3 O).sub.2 P(O)CH.sub.2 CO(CH.sub.2).sub.4 CH.sub.3                                       y)                                                  g) 2. (CH.sub.3 O).sub.2 P(O)CH.sub.2 COCH(C.sub.2 H.sub.5)(CH.sub.2).sub.       3 CF.sub.3             z)                                                     3. (CH.sub.3 O).sub.2 P(O)CH.sub.2 COC(CH.sub.3).sub.2 (CH.sub.2).sub.4        CH.sub.3              aa)                                                    4. (CH.sub.3 O).sub.2 P(O)CH.sub.2 CO(CH.sub.2).sub.3 CF.sub.2                CH.sub.3               bb)                                                 h) 1. (CH.sub.3 O).sub.2 P(O)CH.sub.2 CO(CH.sub.2).sub.4 CH.sub.3                                       cc)                                                    2. (CH.sub.3 O).sub.2 P(O)CH.sub.2 COC(CH.sub.3).sub.2 (CH.sub.2).sub.3        CH.sub.3              dd)                                                 h) 3. (CH.sub.3 O).sub.2 P(O)CH.sub.2 COC(CH.sub.3).sub.2 (CH.sub.2).sub.3        CF.sub.3              ee)                                                    4. (CH.sub.3 O).sub.2 P(O)CH.sub.2 CO(CH.sub.2).sub.4 CF.sub.3                                       ff)                                                    5. (CH.sub.3 O).sub.2 P(O)CH.sub.2 CO(CH.sub.2).sub.3 CF.sub.2                CH.sub.3               gg)                                                    6. (CH.sub.3 O).sub.2 P(O)CH.sub.2 CO(CH.sub.2).sub.8 CH.sub.3                                       hh)                                                 i) 1. (CH.sub.3 O).sub.2 P(O)CH.sub.2 CO(CH.sub.2).sub.8 CF.sub.3                                       ii)                                                 i) 2. (CH.sub.3 O).sub.2 P(O)CH.sub.2 COCH(C.sub.2 H.sub.5)(CH.sub.2).sub.       2 CF.sub.3             jj)                                                 j) 1. (CH.sub.3 O).sub.2 P(O)CH(CH.sub.3)CO(CH.sub.2).sub.2 CF.sub.2             CH.sub.3               kk)                                                    2. (CH.sub.3 O).sub.2 P(O)CH.sub.2 CO(CH.sub.2).sub.4 CH.sub.3                                       ll)                                                 k) 1. (CH.sub.3 O).sub.2 P(O)CH.sub.2 CO(CH.sub.2).sub.4 CH.sub.3                                       mm)                                                    2. (CH.sub.3 O).sub.2 P(O)CH.sub.2 COC(CH.sub.3).sub.2 (CH.sub.2).sub.3        CH.sub.3              nn)                                                 k) 3. (CH.sub.3 O).sub.2 P(O)CH.sub.2 COC(CH.sub.3).sub.2 (CH.sub.2).sub.3        CF.sub.3              oo)                                                    4. (CH.sub.3 O).sub.2 P(O)CH.sub.2 CO(CH.sub.2).sub.4 CF.sub.3                                       pp)                                                    5. (CH.sub.3 O).sub.2 P(O)CH.sub.2 CO(CH.sub.2).sub.3 CF.sub.2                CH.sub.3               qq)                                                    6. (CH.sub.3 O).sub.2 P(O)CH.sub.2 CO(CH.sub.2).sub.8 CH.sub.3                                       rr)                                                 1) 1. (CH.sub.3 O).sub.2 P(O)CH.sub.2 CO(CH.sub.2).sub.4 CH.sub.3                                       ss)                                                    2. (CH.sub.3 O).sub.2 P(O)CH.sub.2 COCH(C.sub.2 H.sub.5)(CH.sub.2).sub.       3 CF.sub.3             tt)                                                 1) 3. (CH.sub.3 O).sub.2 P(O)CH.sub. 2 COC(CH.sub.3).sub.2 (CH.sub.2).sub.       4 CH.sub.3             uu)                                                    4. (CH.sub.3 O).sub.2 P(O)CH.sub.2 CO(CH.sub.2).sub.3 CF.sub.2                CH.sub.3               vv)                                                 m) 1. (CH.sub.3 O).sub.2 P(O)CH.sub.2 CO(CH.sub.2).sub.4 CH.sub.3                                       ww)                                                    2. (CH.sub.3 O).sub.2 P(O)CH.sub.2 COC(CH.sub.3).sub.2 (CH.sub.2).sub.3        CH.sub.3              xx)                                                    3. (CH.sub.3 O).sub.2 P(O)CH.sub.2 COC(CH.sub.3).sub.2 (CH.sub.2).sub.3        CF.sub.3              yy)                                                    4. (CH.sub.3 O).sub.2 P(O)CH.sub.2 CO(CH.sub.2).sub.4 CF.sub.3                                       zz)                                                 m) 5. (CH.sub.3 O).sub.2 P(O)CH.sub.2 CO(CH.sub.2).sub.3 CF.sub.2                CH.sub.3               aaa)                                                   6. (CH.sub.3 O).sub.2 P(O)CH.sub.2 CO(CH.sub.2).sub.8 CH.sub.3                                       bbb)                                                n) 1. (CH.sub.3 O).sub.2 P(O)CH.sub.2 CO(CH.sub.2).sub.8 CF.sub.3                                       ccc)                                                   2. (CH.sub.3 O).sub.2 P(O)CH.sub.2 COCH(C.sub.2 H.sub.5)(CH.sub.2).sub.       2 CF.sub.3             ddd)                                                o) 1. (CH.sub.3 O).sub.2 P(O)CH(CH.sub.3)CO(CH.sub.2).sub.2 CF.sub.2             CH.sub.3               eee)                                                   2. (CH.sub.3 O).sub.2 P(O)CH.sub.2 CO(CH.sub.2).sub.4 CH.sub.3                                       fff)                                                p) 1. (CH.sub.3 O).sub.2 P(O)CH.sub.2 CO(CH.sub.2).sub.4 CH.sub.3                                       (g.sup.3)                                              2. (CH.sub.3 O).sub.2 P(O)CH.sub.2 COC(CH.sub.3).sub.2 (CH.sub.2).sub.3        CH.sub.3              (h.sup.3)                                              3. (CH.sub.3 O).sub.2 P(O)CH.sub.2 CO(CH.sub.2).sub.4 CF.sub.3                                       (i.sup.3)                                              4. (CH.sub.3 O).sub.2 P(O)CH.sub.2 CO(CH.sub.2).sub. 3 CF.sub.2               CH.sub.3               (j.sup.3)                                              5. (CH.sub.3 O).sub.2 P(O)CH.sub.2 CO(CH.sub.2).sub.8 CH.sub.3                                       (k.sup.3)                                           q) 1. (CH.sub.3 O).sub.2 P(O)CH.sub.2 CO(CH.sub.2).sub.4 CH.sub.3                                       (l.sup.3)                                              2. (CH.sub.3 O).sub.2 P(O)CH.sub.2 COC(CH.sub.3).sub.2 (CH.sub.2).sub.3        CH.sub.3              (m.sup.3)                                              3. (CH.sub.3 O).sub.2 P(O)CH.sub.2 COC(CH.sub.3).sub.2 (CH.sub.2).sub.3        CF.sub.3              n.sup.3)                                               4. (CH.sub.3 O).sub.2 P(O)CH.sub.2 CO(CH.sub.2).sub.4 CF.sub.3                                       o.sup.3)                                               5. (CH.sub.3 O).sub.2 P(O)CH.sub.2 CO(CH.sub.2).sub.3 CF.sub.2                CH.sub.3               p.sup.3)                                               6. (CH.sub.3 O).sub.2 P(O)CH.sub.2 CO(CH.sub.2).sub.8 CH.sub.3                                       q.sup.3)                                            r) 1. (CH.sub.3 O).sub.2 P(O)CH.sub.2 CO(CH.sub.2).sub.4 CH.sub.3                                       r.sup.3)                                               2. (CH.sub.3 O).sub.2 1. 2COC(CH.sub.3).sub.2 (CH.sub.2).sub.3                CH.sub.3               s.sup.3)                                               3. (CH.sub.3 O).sub.2 P(O)CH.sub.2 CO(CH.sub.2).sub.4 CF.sub.3                                       t.sup.3)                                               4. (CH.sub.3 O).sub.2 P(O)CH.sub.2 CO(CH.sub.2).sub.3 CF.sub.2                CH.sub.3               u.sup.3)                                               5. (CH.sub.3 O).sub.2 P(O)CH.sub.2 CO(CH.sub.2).sub.8 CH.sub.3                                       v.sup.3)                                               G                          H                                               __________________________________________________________________________    a) 1. Zn(BH.sub.4).sub.2  a)                                                     2. CH.sub.3 MgBr       b)                                                  b) 1. Zn(BH.sub.4).sub.2  c)                                                     2. Na/THF/t-BuOH; NaBH.sub.4                                                                         d)                                                  c) 1. Zn(BH.sub.4).sub.2  e)                                                     2. CH.sub.3 CH.sub.2 MgBr                                                                            f)                                                  c) 3. Na/THF/t-BuOH; CH.sub.2 =CHMgBr                                                                   g)                                                  d) 1. Zn(BH.sub.4).sub.2  h)                                                     2. CH.sub.3 MgBr       i)                                                  e) 1. Zn(BH.sub.4).sub.2  j)                                                     2. Na/THF/t-BuOH; HC.tbd.C.sup.-Li.sup.+                                                             k)                                                  f) 1. Zn(BH.sub.4).sub.2  l)                                                  g) 1. Zn(BH.sub.4).sub.2  m)                                                     2. CH.sub.2 CH.sub.2 MgBr                                                                            n)                                                  h) 1. Zn(BH.sub.4).sub.2  o)                                                     2. CH.sub.3 MgBr       p)                                                  i) 1. Zn(BH.sub.4).sub.2  q)                                                  j) 1. Zn(BH.sub.4).sub.2  r)                                                  j) 2. CH.sub.3 MgBr       s)                                                     3. Na/THF/t-BuOH; CH.sub.2 =CHMgBr                                                                   t)                                                  k) 1. Zn(BH.sub.4).sub.2  u)                                                  l) 1. Zn(BH.sub.4).sub.2  v)                                                     2. Na/THF/t-BuOH; NaBH.sub.4                                                                         w)                                                  m) 1. Zn(BH.sub.4).sub.2  x)                                                  m) 2. CH.sub.3 MgBr       y)                                                  n) 1. Zn(BH.sub.4).sub.2  z)                                                     2. (n)C.sub.4 H.sub.9 MgBr                                                                           aa)                                                 o) 1. Zn(BH.sub.4).sub.2  bb)                                                    2. HC.tbd.C.sup.-Li.sup.+                                                                            cc)                                                 p) 1. Zn(BH.sub.4).sub.2  dd)                                                 q) 1. Zn(BH.sub.4).sub.2  ee)                                                 r) 1. Zn(BH.sub.4).sub.2  ff)                                                    2. nC.sub.3 H.sub.7 MgBr                                                                             gg)                                                 s) 1. Zn(BH.sub.4).sub.2  hh)                                                    2. CH.sub.3 MgBr       ii)                                                 t) 1. Zn(BH.sub.4).sub.2  jj)                                                 u) 1. Zn(BH.sub.4).sub.2  kk)                                                 v) 1. Zn(BH.sub.4).sub.2  ll)                                                    2. CH.sub.3 MgBr       mm)                                                    3. Na/THF/t-BuOH; CH.sub.2 =CHMgBr                                                                   nn)                                                 w) 1. Zn(BH.sub.4).sub.2  oo)                                                 w  2. C.sub.2 H.sub.5 MgBr                                                                              pp)                                                 x) 1. Zn(BH.sub.4).sub.2  qq)                                                 y) 1. Zn(BH.sub.4).sub.2  rr)                                                    2. C.sub.2 H.sub.5 MgBr                                                                              ss)                                                 z) 1. Zn(BH.sub.4).sub.2  tt)                                                 aa)                                                                              1. Zn(BH.sub.4).sub.2  uu)                                                 bb)                                                                              1. Zn(BH.sub.4).sub.2  vv)                                                    2. CH.sub.3 MgBr       ww)                                                 cc)                                                                              1. Zn(BH.sub.4).sub.2  xx)                                                    2. CH.sub.3 MgBr       yy)                                                 cc 3. Na/THF/t-BuOH; HC.tbd.C.sup.-Li.sup.+                                                             zz)                                                 dd)                                                                              1. Zn(BH.sub.4).sub.2  aaa)                                                ee)                                                                              1. Zn(BH.sub.4).sub.2  bbb)                                                ff)                                                                              1. Zn(BH.sub.4).sub.2  ccc)                                                   2. C.sub.2 H.sub.5 MgBr                                                                              ddd)                                                gg)                                                                              1. Zn(BH.sub.4).sub.2  eee)                                                gg)                                                                              2. CH.sub.3 MgBr       fff)                                                hh)                                                                              1. Na/THF/t-BuOH; CH.sub.2 =CHMgBr                                                                   ggg)                                                ii)                                                                              1. Zn(BH.sub.4).sub.2  hhh)                                                   2. nC.sub.4 H.sub.9 MgBr                                                                             iii)                                                jj)                                                                              1. Zn(BH.sub.4).sub.2  jjj)                                                kk)                                                                              1. Zn(BH.sub.4).sub.2  kkk)                                                ll)                                                                              1. Zn(BH.sub.4).sub.2  lll)                                                   2. Na/THF/t-BuOH; C.sub.2 H.sub.5 MgBr                                                               mmm)                                                mm)                                                                              1. Zn(BH.sub.4).sub.2  nnn)                                                   2. CH.sub.3 MgBr       ooo)                                                nn)                                                                              1. Zn(BH.sub.4).sub.2  ppp)                                                oo)                                                                              1. CH.sub.3 MgBr       qqq)                                                pp)                                                                              1. Zn(BH.sub.4).sub.2  rrr)                                                   2. C.sub.2 H.sub.5 MgBr                                                                              sss)                                                qq)                                                                              1. Zn(BH.sub.4).sub.2  ttt)                                                   2. CH.sub.3 MgBr       uuu)                                                rr)                                                                              1. Zn(BH.sub.4).sub.2  vvv)                                                   2. nC.sub.4 H.sub.9 MgBr                                                                             www)                                                ss)                                                                              1. Zn(BH.sub.4).sub.2  xxx)                                                   2. CH.sub.3 MgBr       yyy)                                                tt)                                                                              1. Zn(BH.sub.4).sub.2  zzz)                                                uu)                                                                              1. Zn(BH.sub.4).sub.2  a.sup.4)                                            vv)                                                                              1. Zn(BH.sub.4).sub.2  b.sup.4)                                               2. C.sub.2 H.sub.5 MgBr                                                                              c.sup.4)                                            ww)                                                                              1. Zn(BH.sub.4).sub.2  d.sup.4)                                               2. CH.sub.3 MgBr       e.sup.4)                                            xx)                                                                              1. Zn(BH.sub.4).sub.2  f.sup.4)                                            yy)                                                                              1. Zn(BH.sub.4).sub.2  g.sup.4)                                            zz)                                                                              1. Zn(BH.sub.4).sub.2  h.sup.4)                                               2. CH.sub.3 MgBr       i.sup.4)                                            aaa)                                                                             1. Zn(BH.sub.4).sub.2  j.sup.4)                                               2. C.sub.2 H.sub.5 MgBr                                                                              k.sup.4)                                            bbb)                                                                             1. Zn(BH.sub.4).sub.2  l.sup.4)                                            ccc)                                                                             1. Zn(BH.sub.4).sub.2  m.sup.4)                                               2. CH.sub.3 MgBr       n.sup.4)                                            ddd)                                                                             1. Zn(BH.sub.4).sub.2  o.sup.4)                                            eee)                                                                             1. Zn(BH.sub.4).sub.2  p.sup.4)                                            fff)                                                                             1. Zn(BH.sub.4).sub.2  q.sup.4)                                               2. nC.sub.3 H.sub.7 MgBr                                                                             r.sup.4)                                            g.sup.3)                                                                         1. Zn(BH.sub.4).sub.2  s.sup.4 )                                           )  2. CH.sub.3 MgBr       t.sup.4)                                            h.sup.3)                                                                         1. Zn(BH.sub.4).sub.2  u.sup.4)                                            )  2. CH.sub.3 MgBr       v.sup.4)                                            i.sup.3)                                                                         1. Zn(BH.sub.4).sub.2  w.sup.4)                                            )  2. CH.sub.3 CH.sub.2 MgBr                                                                            x.sup.4)                                            j.sup.3)                                                                         1. Zn(BH.sub.4).sub.2  y.sup.4)                                            )  2. CH.sub.3 MgBr       z.sup.4)                                            k.sup.3)                                                                         1. Zn(BH.sub.4).sub.2  a.sup.5)                                            )  2. CH.sub.3 MgBr       b.sup.5)                                            1.sup.3)                                                                         1. Zn(BH.sub.4).sub.2  c.sup.5)                                            )  2. CH.sub.3 MgBr       d.sup.5)                                            m.sup.3)                                                                         Zn(BH.sub.4).sub.2     e.sup.5)                                            n.sup.3)                                                                         Zn(BH.sub.4).sub.2     f.sup.5)                                            o.sup.3)                                                                         1. Zn(BH.sub.4).sub.2  g.sup.5)                                            )  2. CH.sub.3 CH.sub.2 MgBr                                                                            h.sup.5)                                            p.sup.3)                                                                         1. Zn(BH.sub.4).sub.2  i.sup.5)                                            )  2. CH.sub.3 MgBr       j.sup.5)                                            q.sup.3)                                                                         1. Zn(BH.sub.4).sub.2  k.sup.5)                                            )  2. CH.sub.3 MgBr       l.sup.5)                                            r.sup.3)                                                                         1. Zn(BH.sub.4).sub.2  m.sup.5)                                            )  2. CH.sub.3 MgBr       n.sup.5)                                            s.sup.3)                                                                         Zn(BH.sub.4).sub.2     o.sup.5)                                            t.sup.3)                                                                         1. Zn(BH.sub.4).sub.2  p.sup.5)                                            )  2. CH.sub.3 MgBr       q.sup.5)                                            u.sup.3)                                                                         1. Zn(BH.sub.4).sub.2  r.sup.5)                                            )  2. CH.sub.3 CH.sub.2 MgBr                                                                            s.sup.5)                                            v.sup.3)                                                                         Zn(BH.sub.4).sub.2     t.sup.5)                                               I                          J                                               __________________________________________________________________________    a)    --                  a)                                                  b) C.sub.2 H.sub.5 I, NaH b)                                                  c) CH.sub.3 I, NaH        c)                                                  d) PhCH.sub.2 I, NaH      d)                                                  e) CH.sub.3 COCl, (C.sub.2 H.sub.5).sub.3 N                                                             e)                                                  f     --                  f)                                                  g) CH.sub.3 I, NaH        g)                                                  h)    --                  h)                                                  i) CH.sub.3 I, NaH        i)                                                  j)    --                  j)                                                  k) PhCH.sub.2 I, NaH      k)                                                  l) CH.sub.3 COCl, (C.sub.2 H.sub.5).sub.3 N                                                             l)                                                  m)    --                  m)                                                  n) C.sub.2 H.sub.5 I, NaH n)                                                  o)    --                  o)                                                  p) CH.sub.3 I, NaH        p)                                                  q)    --                  q)                                                  r)    --                  r)                                                  s) CH.sub.3 COCl, (C.sub.2 H.sub.5).sub.3 N                                                             s)                                                  t) C.sub.2 H.sub.5 I, NaH t)                                                  u)    --                  u)                                                  v)    --                  v)                                                  w) PhCH.sub.2 I, NaH      w)                                                  x)    --                  x)                                                  y) CH.sub.3 I, NaH        y)                                                  z) CH.sub.3 COCl, (C.sub.2 H.sub.5).sub.3 N                                                             z)                                                  a.sup.2)                                                                         C.sub.2 H.sub.5 I, NaH a.sup.2)                                            b.sup.2)                                                                         PhCH.sub.2 I, NaH      b.sup.2)                                            c.sup.2)                                                                         CH.sub.3 I, NaH        c.sup.2)                                            d.sup.2)                                                                         PhCH.sub.2 I, NaH      d.sup.2)                                            e.sup.2)                                                                         CH.sub.3 COCl, (C.sub.2 H.sub.5).sub.3 N                                                             e.sup.2)                                            f.sup.2)                                                                            --                  f.sup.2)                                            g.sup.2)                                                                         C.sub.2 H.sub.5 I, NaH g.sup.2)                                            h.sup.2)                                                                             --                 h.sup.2)                                            i.sup.2)                                                                         CH.sub.3 COCl, (C.sub.2 H.sub.5).sub.3 N                                                             i.sup.2)                                            j.sup.2)                                                                            --                  j.sup.2)                                            k.sup.2)                                                                         CH.sub.3 I, NaH        k.sup.2)                                            l.sup.2)                                                                            --                  l.sup.2)                                            m.sup.2)                                                                         C.sub.2 H.sub.5 I, NaH m.sup.2)                                            n.sup.2)                                                                         CH.sub.3 COCl, (C.sub.2 H.sub.5).sub.3 N                                                             n.sup.2)                                            o.sup.2)                                                                            --                  o.sup.2)                                            p.sup.2)                                                                         CH.sub.3 I, NaH        p.sup.2)                                            q.sup.2)                                                                         CH.sub.3 COCl, (C.sub. 2 H.sub.5).sub.3 N                                                            q.sup.2)                                            r.sup.2)                                                                         CH.sub.3 I, NaH        r.sup.2)                                            s.sup.2)                                                                         PhCH.sub.2 I, NaH      s.sup.2)                                            t.sup.2)                                                                            --                  t.sup.2)                                            u.sup.2)                                                                            --                  u.sup.2)                                            v.sup.2)                                                                         C.sub.2 H.sub.5 I, NaH v.sup.2)                                            w.sup.2)                                                                         CH.sub.3 I, NaH        w.sup.2)                                            x.sup.2)                                                                            --                  x.sup.2)                                            y.sup.2)                                                                         CH.sub.3 COCl, (C.sub.2 H.sub.5).sub.3 N                                                             y.sup.2)                                            z.sup.2)                                                                         CH.sub.3 I, NaH        z.sup.2)                                            a.sup.3)                                                                            --                  a.sup.3)                                            b.sup.3)                                                                         C.sub.2 H.sub.5 I, NaH b.sup.3)                                            c.sup.3)                                                                         CH.sub.3 I, NaH        c.sup.3)                                            d.sup.3)                                                                         CH.sub.3 COCl, (C.sub.2 H.sub.5).sub.3 N                                                             d.sup.3)                                            e.sup.3)                                                                            --                  e.sup.3)                                            f.sup.3)                                                                         CH.sub.3 I, NaH        f.sup.3)                                            g.sup.3)                                                                         C.sub.2 H.sub.5 COCl, (C.sub.2 H.sub.5).sub.3 N                                                      g.sup.3)                                            h.sup.3)                                                                         C.sub.2 H.sub.5 I, NaH h.sup.3)                                            i.sup.3)                                                                         CH.sub.3 I, NaH        i.sup.3)                                            j.sup.3)                                                                            --                  j.sup.3)                                            k.sup.3)                                                                         CH.sub.3 COCl, (C.sub.2 H.sub.5).sub.3 N                                                             k.sup.3)                                            l.sup.3)                                                                            --                  l.sup.3)                                            m.sup.3)                                                                         CH.sub.3 I, NaH        m.sup.3)                                            n.sup.3)                                                                            --                  n.sup.3)                                            o.sup.3                                                                          (CH.sub.3).sub.2 CHCOCl, (C.sub.2 H.sub.5).sub.3 N                                                   o.sup.3)                                            p.sup.3)                                                                            --                  p.sup.3)                                            q.sup.3)                                                                         CH.sub.3 COCl, (C.sub.2 H.sub.5).sub.3 N                                                             q.sup.3)                                            r.sup.3)                                                                            --                  r.sup.3)                                            s.sup.3)                                                                         CH.sub.3 I, NaH        s.sup.3)                                            t.sup.3)                                                                            --                  t.sup.3)                                            u.sup.3)                                                                         C.sub.2 H.sub.5 COCl, (C.sub.2 H.sub.5).sub.3 N                                                      u.sup.3)                                            v.sup.3)                                                                         C.sub.2 H.sub.5 I, NaH v.sup.3)                                            w.sup.3)                                                                         CH.sub.3 COCl, (C.sub.2 H.sub.5).sub.3 N                                                             w.sup.3)                                            x.sup.3)                                                                            --                  x.sup.3)                                            y.sup.3)                                                                         CH.sub.3 I, NaH        y.sup.3)                                            z.sup.3)                                                                         nC.sub.3 H.sub.7 COCl, (C.sub.2 H.sub.5).sub.3 N                                                     z.sup.3)                                            a.sup.4)                                                                            --                  a.sup.4)                                            b.sup.4)                                                                         C.sub.2 H.sub.5 I, NaH b.sup.4)                                            c.sup.4)                                                                         CH.sub.3 COCl, (C.sub.2 H.sub.5).sub.3 N                                                             c.sup.4)                                            d.sup.4)                                                                            --                  d.sup.4)                                            e.sup.4)                                                                         CH.sub.3 I, NaH        e.sup.4)                                            f.sup.4)                                                                         (CH.sub.3).sub.2 CHCOCl, (C.sub.2 H.sub.5).sub.3 N                                                   f.sup.4)                                            g.sup.4)                                                                            --                  g.sup.4)                                            h.sup.4)                                                                            --                  h.sup.4)                                            i.sup.4)                                                                         CH.sub.3 I, NaH        i.sup.4)                                            j.sup.4)                                                                            --                  j.sup.4)                                            k.sup.4)                                                                         CH.sub.3 COCl, (C.sub.2 H.sub.5).sub.3 N                                                             k.sup.4)                                            l.sup.4)                                                                         C.sub.2 H.sub.5 I, (C.sub.2 H.sub.5).sub.3 N                                                         l.sup.4)                                            m.sup.4)                                                                         C.sub.2 H.sub.5 COCl, (C.sub.2 H.sub.5).sub.3 N                                                      m.sup.4)                                            n.sup.4)                                                                         CH.sub.3 COCl, (C.sub.2 H.sub.5).sub.3 N                                                             n.sup.4)                                            o.sup.4)                                                                            --                  o.sup.4)                                            p.sup.4)                                                                         nC.sub.3 H.sub.7 COCl, (C.sub.2 H.sub.5).sub.3 N                                                     p.sup.4)                                            q.sup.4)                                                                            --                  q.sup.4)                                            r.sup.4)                                                                         CH.sub.3 I, NaH        r.sup.4)                                            s.sup. 4)                                                                           --                  s.sup.4)                                            t.sup.4)                                                                         C.sub.2 H.sub.5 I, NaH t.sup.4)                                            u.sup.4)                                                                         CH.sub.3 I, NaH        u.sup.4)                                            v.sup.4)                                                                            --                  v.sup.4)                                            w.sup.4)                                                                         CH.sub.3 COCl, (C.sub.2 H.sub.5).sub.3 N                                                             w.sup.4)                                            x.sup.4)                                                                         CH.sub.3 COCl, (C.sub.2 H.sub.5).sub.3 N                                                             x.sup.4)                                            y.sup.4)                                                                            --                  y.sup.4)                                            z.sup.4)                                                                         CH.sub.3 I, NaH        z.sup.4)                                            a.sup.5)                                                                            --                  a.sup.5)                                            b.sup.5)                                                                         CH.sub.3 COCl, (C.sub.2 H.sub.5).sub.3 N                                                             b.sup.5)                                            c.sup.5)                                                                            --                  c.sup.5)                                            d.sup.5)                                                                            --                  d.sup.5)                                            e.sup.5)                                                                         CH.sub.3 COCl, (C.sub.2 H.sub.5).sub.3 N                                                             e.sup.5)                                            f.sup.5)                                                                            --                  f.sup.5)                                            g.sup.5)                                                                         CH.sub.3 I, NaH        g.sup.5)                                            h.sup.5)                                                                            --                  h.sup.5)                                            i.sup.5)                                                                            --                  i.sup.5)                                            j.sup.5)                                                                         CH.sub.3 COCl, (C.sub.2 H.sub.5).sub.3 N                                                             j.sup.5)                                            k.sup.5)                                                                            --                  k.sup.5)                                            l.sup.5)                                                                         CH.sub.3 COCl, (C.sub.2 H.sub.5).sub.3 N                                                             l.sup.5)                                            m.sup.5)                                                                            --                  m.sup.5)                                            n.sup.5)                                                                         CH.sub.3 I, NaH        n.sup.5)                                            o.sup.5)                                                                            --                  o.sup.5)                                            p.sup.5)                                                                         C.sub.2 H.sub.5 I, NaH p.sup.5)                                            q.sup.5)                                                                         CH.sub.3 COCl, (C.sub.2 H.sub.5).sub.3 N                                                             q.sup.5)                                            r.sup.5)                                                                         PhCH.sub.2 I, NaH      r.sup.5)                                            s.sup.5)                                                                            --                  s.sup.5)                                            t.sup.5)                                                                         CH.sub.3 COCl, (C.sub.2 H.sub.5).sub.3 N                                                             t.sup.5)                                               K                          L                                               __________________________________________________________________________    a) CH.sub.3 OH            a)                                                  b)    --                  b)                                                  c) nC.sub.10 H.sub.21 OH  c)                                                  d) NaOH                   d)                                                  e) H.sub.3 N.sup.+C(CH.sub.2 OH).sub.3 Cl.sup.-                                                         e)                                                  f) NaOH                   f)                                                  g) C.sub.2 H.sub.5 OH     g)                                                  h)    --                  h)                                                  i) PhCH.sub.2 OH          i)                                                  j) LiOH                   j)                                                  k) CH.sub.3 OH            k)                                                  l) cC.sub.6 H.sub.11 OH   l)                                                  m) NaOH                   m)                                                  n) NaOH                   n)                                                  o)    --                  o)                                                  p) CH.sub.3 OH            p)                                                  q) C.sub.2 H.sub.5 OH     q)                                                  r) NaOH                   r)                                                  s) (nC.sub.4 H.sub.9).sub.4 N.sup.+OH.sup.-                                                             s)                                                  t) LiOH                   t)                                                  u)    --                  u)                                                  v) NaOH                   v)                                                  w) H.sub.3 N.sup.+C(CH.sub.2 OH).sub.3 .sup.-Cl                                                         w)                                                  x) CH.sub.3 OH            x)                                                  y) CH.sub.3 OH            y)                                                  z) LiOH                   z)                                                  a.sup.2)                                                                         C.sub.2 H.sub.5 OH     a.sup.2)                                            b.sup.2)                                                                         PhCH.sub.2 OH          b.sup.2)                                            c.sup.2 )                                                                        (nC.sub.4 H.sub.9).sub.4 N.sup.+OH.sup.-                                                             c.sup.2)                                            d.sup.2)                                                                         NaOH                   d.sup.2)                                            e.sup.2)                                                                            --                  e.sup.2)                                            f.sup.2)                                                                            --                  f.sup.2)                                            g.sup.2)                                                                         C.sub.2 H.sub.5 OH     g.sup.2)                                            h.sup.2)                                                                            --                  h.sup.2)                                            i.sup.2)                                                                         CH.sub.3 OH            i.sup.2)                                            j.sup.2)                                                                         NaOH                   j.sup.2)                                            k.sup.2)                                                                         cC.sub.6 H.sub.11 OH   k.sup.2)                                            l.sup.2)                                                                         LiOH                   l.sup.2)                                            m.sup.2)                                                                         C.sub.2 H.sub.5 OH     m.sup.2)                                            n.sup.2)                                                                         nC.sub.10 H.sub.21 OH  n.sup.2)                                            o.sup.2)                                                                            --                  o.sup.2)                                            p.sup.2)                                                                         PhCH.sub.2 OH          p.sup.2)                                            q.sup.2)                                                                         NaOH                   q.sup.2)                                            r.sup.2)                                                                         CH.sub.3 OH            r.sup.2)                                            s.sup.2)                                                                         H.sub.3 N.sup.+C(CH.sub.2 OH).sub.3 Cl.sup.-                                                         s.sup.2)                                            t.sup.2)                                                                            --                  t.sup.2)                                            u.sup.2)                                                                         LiOH                   u.sup.2)                                            v.sup.2 )                                                                        C.sub.2 H.sub.5 OH     v.sup.2)                                            w.sup.2)                                                                         nC.sub.10 H.sub.21 OH  w.sup.2)                                            x.sup.2)                                                                            --                  x.sup.2)                                            y.sup.2)                                                                         NaOH                   y.sup.2)                                            z.sup.2                                                                          C.sub.2 H.sub.5 OH     z.sup.2)                                            a.sup.3)                                                                         CH.sub.3 OH            a.sup.3)                                            b.sup.3)                                                                            --                  b.sup.3)                                            c.sup.3)                                                                         LiOH                   c.sup.3)                                            d.sup.3)                                                                         c-C.sub.5 H.sub.9 OH   d.sup.3)                                            e.sup.3)                                                                            --                  e.sup.3)                                            f.sup.3)                                                                         LiOH                   f.sup.3)                                            g.sup.3)                                                                         (nC.sub.4 H.sub.9).sub.4 N.sup.+OH.sup.-                                                             g.sup.3)                                            h.sup.3)                                                                         H.sub.3 N.sup.+C(CH.sub.2 OH).sub.3 .sup.-Cl                                                         h.sup.3)                                            i.sup.3)                                                                         PhCH.sub.2 OH          i.sup.3)                                            j.sup.3)                                                                         NaOH                   j.sup.3)                                            k.sup.3)                                                                            --                  k.sup.3)                                            l.sup.3)                                                                         (CH.sub.3).sub.2 CHOH  l.sup.3)                                            m.sup.3)                                                                         CH.sub.3 OH            m.sup.3)                                            n.sup.3)                                                                            --                  n.sup.3)                                            o.sup.3)                                                                            --                  o.sup.3)                                            p.sup.3)                                                                         nC.sub.10 H.sub.21 OH  p.sup.3)                                            q.sup.3)                                                                         LiOH                   q.sup.3)                                            r.sup.3)                                                                         cC.sub.6 H.sub.11 OH   r.sup.3)                                            s.sup.3)                                                                         NaOH                   s.sup.3)                                            t.sup.3)                                                                         (nC.sub.4 H.sub.9).sub.4 N.sup.+OH.sup.-                                                             t.sup.3)                                            u.sup.3)                                                                            --                  u.sup.3)                                            v.sup.3)                                                                         NaOH                   v.sup.3)                                            w.sup.3)                                                                         LiOH                   w.sup.3)                                            x.sup.3)                                                                            --                  x.sup.3)                                            y.sup.3)                                                                         CH.sub.3 OH            y.sup.3)                                            z.sup.3)                                                                            --                  z.sup.3)                                            a.sup.4)                                                                         NaOH                   a.sup.4)                                            b.sup.4)                                                                         CH.sub.3 OH            b.sup.4)                                            c.sup.4)                                                                         PhCH.sub.2 OH          c.sup.4)                                            d.sup.4)                                                                         LiOH                   d.sup.4)                                            e.sup.4)                                                                         (CH.sub.3).sub.2 CHOH  e.sup.4)                                            f.sup.4)                                                                         KOH                    f.sup.4)                                            g.sup.4)                                                                         C.sub.2 H.sub.5 OH     g.sup.4)                                            h.sup.4)                                                                            --                  h.sup.4 )                                           i.sup.4)                                                                         NaOH                   i.sup.4)                                            j.sup.4)                                                                         c-C.sub.5 H.sub.9 OH   j.sup.4)                                            k.sup.4)                                                                         LiOH                   k.sup.4)                                            l.sup.4)                                                                         n-C.sub.10 H.sub.21 OH l.sup.4)                                            m.sup.4)                                                                         H.sub.3 N.sup.+C(CH.sub.2 OH).sub.3 Cl.sup.-                                                         m.sup.4)                                            n.sup.4)                                                                            --                  n.sup.4)                                            o.sup.4)                                                                         (nC.sub.3 H.sub.7).sub.4 N.sup.+OH.sup.-                                   p.sup.4)                                                                         NaOH                   p.sup.4)                                            q.sup.4)                                                                         LiOH                   q.sup.4)                                            r.sup. 4)                                                                        C.sub.2 H.sub.5 OH     r.sup.4)                                            s.sup.4)                                                                         CH.sub.3 OH            s.sup.4)                                            t.sup.4)                                                                         NaOH                   t.sup.4)                                            u.sup.4)                                                                         H.sub.3 N.sup.+C(CH.sub.2 OH).sub.3 Cl.sup.-                                                         u.sup.4)                                            v.sup.4)                                                                            --                  v.sup.4)                                            w.sup.4)                                                                         CH.sub.3 OH            w.sup.4)                                            x.sup.4)                                                                            --                  x.sup.4)                                            y.sup.4)                                                                         LiOH                   y.sup.4)                                            z.sup.4)                                                                         CH.sub.3 OH            z.sup.4)                                            a.sup.5)                                                                         LiOH                   a.sup.5)                                            b.sup.5)                                                                         H.sub.3 N.sup.+C(CH.sub.2 OH).sub.3 Cl.sup.-                                                         b.sup.5)                                            c.sup.5)                                                                         CH.sub.3 OH            c.sup.5)                                            d.sup.5)                                                                         (nC.sub.4 H.sub.9).sub.4 N.sup.+OH.sup.-                                                             d.sup.5)                                            e.sup.5)                                                                         NaOH                   e.sup.5)                                            f.sup.5)                                                                            --                  f.sup.5)                                            g.sup.5)                                                                         KOH                    g.sup.5)                                            h.sup.5)                                                                         CH.sub.3 OH            h.sup.5)                                            i.sup.5)                                                                         CH.sub.3 OH            i.sup.5)                                            j.sup.5)                                                                             --                 j.sup.5)                                            k.sup.5)                                                                         CH.sub.3 OH            k.sup.5)                                            l.sup.5)                                                                         H.sub.3 N.sup.+C(CH.sub.2 OH).sub.3 .sup.-Cl                                                         l.sup.5)                                            m.sup.5)                                                                            --                  m.sup.5)                                            n.sup.5)                                                                         CH.sub.3 OH            n.sup.5)                                            o.sup.5)                                                                            --                  o.sup.5)                                            p.sup.5)                                                                         C.sub.2 H.sub.5 OH     p.sup.5)                                            q.sup.5)                                                                         H.sub.3 N.sup.+C(CH.sub.2 OH).sub.3 Cl.sup.-                                                         q.sup.5)                                            r.sup. 5)                                                                           --                  r.sup.5)                                            s.sup.5)                                                                         NaOH                   s.sup.5)                                            t.sup.5)                                                                            --                  t.sup.5)                                               M                          N                                               __________________________________________________________________________    h.sup.2)                                                                            --                  h.sup.2)                                            i.sup.2)                                                                            --                  i.sup.2)                                            j.sup.2)                                                                            --                  j.sup.2)                                            k.sup.2)                                                                         C.sub.2 H.sub.5 I, NaH k.sup.2)                                            l.sup.2)                                                                         CH.sub.3 COCl, (C.sub.2 H.sub.5).sub.3 N                                                             l.sup.2)                                            m.sup.2)                                                                         PhCH.sub.2 I, NaH      m.sup.2)                                            n.sup.2)                                                                         (CH.sub.3).sub.2 CHCOCl, (C.sub.2 H.sub.5).sub.3 N                                                   n.sup.2)                                            o.sup.2)                                                                            --                  o.sup.2)                                            p.sup.2)                                                                         C.sub.2 H.sub.5 I, NaH p.sup.2)                                            q.sup.2)                                                                            --                  q.sup.2)                                            r.sup.2)                                                                         CH.sub.3 COCl, (C.sub.2 H.sub.5).sub.3 N                                                             r.sup.2)                                            s.sup.2)                                                                            --                  s.sup.2)                                            t.sup.2)                                                                            --                  t.sup.2)                                            u.sup.2)                                                                            --                  u.sup.2)                                            v.sup. 2)                                                                        nC.sub.3 H.sub.7 COCl, (C.sub.2 H.sub.5).sub.3 N                                                     v.sup.2)                                            w.sup.2)                                                                            --                  w.sup.2)                                            x.sup.2                                                                             --                  x.sup.2)                                            y.sup.2)                                                                         C.sub.2 H.sub.5 COCl, (C.sub.2 H.sub.5).sub.3 N                                                      y.sup.2)                                            z.sup.2)                                                                            --                  z.sup.2)                                            a.sup.3)                                                                            --                  a.sup.3)                                            b.sup.3)                                                                         CH.sub.3 COCl, (C.sub.2 H.sub.5).sub.3 N                                                             b.sup.3)                                            c.sup.3)                                                                         CH.sub.3 COCl, (C.sub.2 H.sub.5).sub.3 N                                                             c.sup.3)                                            d.sup. 3)                                                                        CH.sub.3 I, NaH        d.sup.3)                                            e.sup.3)                                                                            --                  e.sup.3)                                            f.sup.3)                                                                         (CH.sub.3).sub.2 CHCOCl, (C.sub.2 H.sub.5).sub.3 N                                                   f.sup.3)                                            g.sup.3)                                                                            --                  g.sup.3)                                            h.sup.3)                                                                            --                  h.sup.3)                                            i.sup.3)                                                                         C.sub.2 H.sub.5 I, NaH i.sup.3)                                            j.sup.3)                                                                            --                  j.sup.3)                                            k.sup.3)                                                                         (CH.sub.3).sub.2 CHCOCl, (C.sub.2 H.sub.5).sub.3 N                                                   k.sup.3)                                            l.sup.3)                                                                            --                  l.sup.3)                                            m.sup.3)                                                                         CH.sub.3 COCl, (C.sub.2 H.sub.5).sub.3 N                                                             m.sup.3)                                            c.sup.5)                                                                            --                  c.sup.5)                                            d.sup.5)                                                                            --                  d.sup.5)                                            e.sup.5)                                                                         CH.sub.3 I, NaH        e.sup.5)                                            f.sup.5)                                                                            --                  f.sup.5)                                            g.sup.5)                                                                         CH.sub.3 COCl, (C.sub.2 H.sub.5).sub.3 N                                                             g.sup.5)                                            h.sup.5)                                                                            --                  h.sup.5)                                            i.sup.5)                                                                            --                  i.sup.5)                                            j.sup.5)                                                                         C.sub.2 H.sub.5 I, NaH j.sup.5)                                            k.sup.5)                                                                            --                  k.sup.5)                                            l.sup.5)                                                                         PhCH.sub.2 I, NaH      l.sup.5)                                            __________________________________________________________________________

We claim:
 1. A compound of the formula ##SPC15##wherein A is --CH=CH--,--C.tbd.C--, phenylene or --CH₂ --; B is --CH₂ --, <C=O or ##EQU2## D is--CH₃, --CF₂ CH₃ or --CF₃ ; Y is H or --OR⁵ ; R is H; alkyl of 1-10carbons; cycloalkyl of 3-8 carbons; phenyl carbons any substituentsbeing halogen, sulfino, sulfo, sulfamoyl, sulfanilyl, sulfoamino orsulfanilamido; aralkyl of 7-10 carbons; alkaryl of 7-10 carbons; or aphysiologically acceptable cation; R¹, r² and R³ individually are H, CH₃or C₂ H₅ ; R⁴ is H, alkyl of 1-4 carbons, vinyl or ethynyl; R⁵ and R⁶individually are H, CH₃, C₂ H₅, tetrahydropyranyl, benzyl, acyl of 1-4carbons or trialkyl sily in which the alkyl has 1-10 carbons; m and nindividually are whole numbers in the range 1-8; a, b and c individuallyare an optional additional bondwith the provisos that if c is present,only one of a and b is present; if c is absent, only one of a and b ispresent and A is not --C.tbd.C--; if a or b is present, Y is H; and withthe further provisos that if R is tertiary butyl, Y is H,O-tetrahydropyranyl or trialkyl silyl and R⁶ is not tetrahydropyranyl.2. A compound of claim 1 where a is present.
 3. A compound of claim 1where b is present.
 4. The compound of claim 1 which is7-[2-oxo-5-(3-oxo-1-oct-1-enyl)-1-pyrrolidinyl] heptanoic acid
 5. Thetertiary butyl ester of the acid of claim
 4. 6. The compound of claim 1which is 7-[2-oxo-5-(3-hydroxy-1-oct-1-enyl)-1-pyrrolidinyl] heptanoicacid.
 7. The tertiary butyl ester of the acid of claim
 6. 8. Thecompound of claim 1 which is7-[2-oxo-5-(3-hydroxy-3-methyl-1-oct-1-enyl)-1-pyrrolidinyl] heptanoicacid.
 9. The tertiary butyl ester of the acid of claim
 8. 10. A compoundof claim 1 where A is phenylene.
 11. The compound of claim 10 which is3-{4-[2-oxo-5-(3-hydroxy-1-oct-1-enyl)-1-pyrrolidinyl]methylphenyl}propionic acid.
 12. A process comprising the steps ofA. contacting undersubstantially anhydrous conditions in the presence of a base and aninert solvent at a temperature range of -50° to 140°C., a lactam of theformula ##SPC16##with an alkylating agent of the formula

    XCH.sub.2 (A)(CH.sub.2).sub.m CO.sub.2 --C--(CH.sub.3).sub.3

to obtain a product of the formula ##SPC17## B. reacting the product ofstep (A) with sodium bis(2-methoxy-ethoxy)aluminum hydride undersubstantially anhydrous conditions in the presence of an inert solventat a temperature range of -90° to -40°C. to obtain a product of theformula ##SPC18##wherein A is --CH₂ --, --CH=CH--, --C.tbd.C-- orphenylene; Y is H, tetrahydropyranyloxy or trialkylsilyloxy in whichalkyl has 1-10 carbon atoms; X is Br, Cl, I, tosyl, methanesulfonate,p-nitrobenzenesulfonate or trifluoroacetate; m is a whole number from 1to 8; a and b individually are an additional bond with the proviso thatif a or b is present Y is H.
 13. The process of claim 12 in which X isBr.
 14. The process of claim 12 in which the base in step (A) isnonnucleophilic with a pKb of 19 or greater.
 15. The process of claim 12in which step (A) is carried out at -50° to 120°C.
 16. The process ofclaim 12 in which step (B) is carried out at -90° to -50°C.